3-hydroxy-N-methylbenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-hydroxy-N-methyl-benzamide (Step A, 700 mg, 4.6 mmol, 1.0 eq.) in anhydrous DMF (10 mL) was added NaH (200 mg, 5.1 mmol, 1.1 eq.). The reaction was stirred for 10 min. at RT after which 4-chloro-2-nitro-phenylamine (2.0 g, 11.6 mmol, 2.5 eq.) was added. The resulting mixture was heated to 80° C. for 4 h. The reaction was quenched with NaHCO3 (aq.), diluted with CH2Cl2 (50 mL), and washed with 1 N NaOH (25 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-100% EtOAc in hexanes) to give pure 3-(4-amino-3-nitro-phenoxy)-N-methyl-benzamide. was added The reaction was quenched with NaHCO3 (aq.) diluted with CH2Cl2 (50 mL) washed with 1 N NaOH (25 mL) The organic layer was dried over MgSO4 filtered concentrated The crude was further purified by column chromatography (0-100% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-hydroxybenzoic acid (10 g, 72 mmol, 1.0 eq.) in 100 mL of anhydrous dioxane was added SOCl2 (6.5 mL, 72 mmol, 1.0 eq.). The solution was heated to reflux and stirred for 4 h. The solvent was removed and the crude was dissolved in anhydrous THF (100 mL). A solution of 2 M CH3NH2 in THF (7.2 mL, 144 mmol, 2.0 eq.) was added upon which a white suspension was formed. The solvent was evaporated and the residue was dissolved in MTBE, washed with sat. NH4Cl (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-100% EtOAc in hexanes) yielded 3-hydroxy-N-methyl-benzamide. The solution was heated to reflux The solvent was removed the crude was dissolved in anhydrous THF (100 mL) was formed The solvent was evaporated the residue was dissolved in MTBE washed with sat. NH4Cl (aq.) The organic layer was dried (MgSO4) filtered concentrated Further purification by column chromatography (0-100% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-hydroxybenzoic acid (10 g, 72 mmol, 1.0 eq.) in 100 mL of anhydrous dioxane was added SOCl2 (6.5 mL, 72 mmol, 1.0 eq.). The solution was heated to reflux and stirred for 4 h. The solvent was removed and the crude was dissolved in anhydrous THF (100 mL). A solution of 2 M CH3NH2 in THF (7.2 mL, 144 mmol, 2.0 eq.) was added upon which a white suspension was formed. The solvent was evaporated and the residue was dissolved in MTBE, washed with sat. NH4Cl (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-100% EtOAc in hexanes) yielded 3-hydroxy-N-methyl-benzamide. The solution was heated to reflux The solvent was removed the crude was dissolved in anhydrous THF (100 mL) was formed The solvent was evaporated the residue was dissolved in MTBE washed with sat. NH4Cl (aq.) The organic layer was dried (MgSO4) filtered concentrated Further purification by column chromatography (0-100% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-hydroxybenzoic acid (1.3 g, 9.4 mmol) and a ethanolic methylamine solution (33%, 1.5 ml, 12.1 mmol) were stirred at 60° C. for 48 h, then the solvent was evaporated in vacuo, and the residue redissolved in a small volume of ethanol. The product precipitated from the solution by the addition of ethyl acetate. The precipitate was collected by filtration and dried to give the subtitled compound (1.3 g, 91%). the solvent was evaporated in vacuo the residue redissolved in a small volume of ethanol The product precipitated from the solution by the addition of ethyl acetate The precipitate was collected by filtration dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture containing 5-fluoro-2-nitrophenylamine (1 eq), Potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (3-hydroxyphenyl)-N-methylcarboxamide (1 eq) and Potassium carbonate (1.2 eq) and stirred at 90° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel gave N-methyl{4-[3-(methylamino)-4-nitro-phenoxy](2-pyridyl))carboxamide. It was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+=272. The reaction mixture was then concentrated partitioned between ethyl acetate and water The organic layer was separated washed with brine dried filtered concentrated in vacuum to give brown solid Purification on silica gel

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture containing 5-fluoro-2-nitrophenylamine (1 eq), Potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (3-hydroxyphenyl)-N-methylcarboxamide (1 eq) and Potassium carbonate (1.2 eq) and stirred at 90° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel gave N-methyl{4-[3-(methylamino)-4-nitro-phenoxy](2-pyridyl))carboxamide. It was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+=272. The reaction mixture was then concentrated partitioned between ethyl acetate and water The organic layer was separated washed with brine dried filtered concentrated in vacuum to give brown solid Purification on silica gel

Conditions: temp:0.00; pressure:0.00; stir: